Drug monitoring detects under- and overdosing in patients receiving 5-fluorouracil-containing chemotherapy-results of a prospective, multicenter German observational study.

INTRODUCTION: Body surface area (BSA)-based dosing of 5-fluorouracil (5-FU) results in marked inter-individual variability in drug levels, whereas determination of plasma 5-FU concentration and area under the curve (AUC) is a more precise dosing method but has not been integrated into clinical routine. We conducted a multicenter, prospective study to study 5-FU AUC distributions and assess clinical factors predicting therapeutic dosing in patients receiving BSA-dosed 5-FU. METHODS: Between June 2017 and January 2018, a total of 434 patients receiving continuous, infusional BSA-dosed 5-FU from 37 sites in Germany were included. Plasma 5-FU concentration and AUC were measured in venous blood samples at steady state. The primary objective was to determine 5-FU AUC distributions in relation to the target range, which is defined as 20-30 mg × h/l. The second objective was to explore clinical parameters that correlate with achievement of 5-FU AUC target range. RESULTS: The primary tumor was mainly located in the gastrointestinal tract (96.3%), with colorectal cancer being the most common (71.2%) tumor entity. 5-FU was administered as monotherapy (8.1%) or as part of FOLFOX (33.2%), FOLFIRI (26.3%), or other regimens (12.4%). Treatment setting was adjuvant (31.3%) or metastatic (64.5%). The median AUC was 16 mg × h/l. Only 20.3% of patients received 5-FU treatment within the target range, whereas the majority of patients (60.6%) were underdosed and 19.1% of patients were overdosed. In the univariate logistic regression, treatment setting was the only clinical parameter that significantly correlated with achievement of the target range. Patients treated in the metastatic setting had a 2.1 (95% confidence interval 1.186-3.776, P = 0.011) higher odds to reach the target range compared with patients treated in the adjuvant setting. CONCLUSIONS: The majority of patients received suboptimal doses of 5-FU using BSA dosing. Therapeutic drug monitoring of 5-FU is an option for optimized individualized cancer therapy and should be integrated into the clinical practice.

Development of Coagulation Factor XII Antibodies for Inhibiting Vascular Device-Related Thrombosis.

INTRODUCTION: Vascular devices such as stents, hemodialyzers, and membrane oxygenators can activate blood coagulation and often require the use of systemic anticoagulants to selectively prevent intravascular thrombotic/embolic events or extracorporeal device failure. Coagulation factor (F)XII of the contact activation system has been shown to play an important role in initiating vascular device surface-initiated thrombus formation. As FXII is dispensable for hemostasis, targeting the contact activation system holds promise as a significantly safer strategy than traditional antithrombotics for preventing vascular device-associated thrombosis. OBJECTIVE: Generate and characterize anti-FXII monoclonal antibodies that inhibit FXII activation or activity. METHODS: Monoclonal antibodies against FXII were generated in FXII-deficient mice and evaluated for their binding and anticoagulant properties in purified and plasma systems, in whole blood flow-based assays, and in an in vivo non-human primate model of vascular device-initiated thrombus formation. RESULTS: A FXII antibody screen identified over 400 candidates, which were evaluated in binding studies and clotting assays. One non-inhibitor and six inhibitor antibodies were selected for characterization in functional assays. The most potent inhibitory antibody, 1B2, was found to prolong clotting times, inhibit fibrin generation on collagen under shear, and inhibit platelet deposition and fibrin formation in an extracorporeal membrane oxygenator deployed in a non-human primate. CONCLUSION: Selective contact activation inhibitors hold potential as useful tools for research applications as well as safe and effective inhibitors of vascular device-related thrombosis.

Long-term evaluation of community health promotion: using capacity building as an intermediate outcome measure.

OBJECTIVES: Between 2001 and 2012, the health authority of Hamburg-Eimsbüttel carried out a health promotion programme for children and their parents in a disadvantaged neighbourhood called Lenzsiedlung. The programme consisted of different action fields aiming at sustainable establishment of community capacities. STUDY DESIGN: The research goal was the long-term assessment of community capacities with a newly developed instrument 'KEQ' (KEQ = Kapazitätsentwicklung im Quartier/capacity building in small areas/neighbourhoods). Practitioners and researchers wanted to know whether community capacities could be increased, which changes occurred during the programme and whether processes of capacity building could be maintained. Research results were also used for the continuous adjustment of the programme to community needs. METHODS: Three surveys on community capacities were conducted (t1: June 2006 [including a retrospective measurement of t0: 2001]; t2: June 2008; and t3: November 2011), each directed to 40-60 stakeholders of the Lenzsiedlung. The instrument consists of five domains (participation, local leadership, available resources, networking and cooperation and health care) with a total of 51 items. RESULTS: For the community capacities, we found a positive trend from 2001 to 2006 supported by data from a documentary analysis over the same period of time. Then, 2006-2011 was a phase of consolidation with only slight improvements (e.g. in the particularly important domain 'health care'). CONCLUSIONS: The results show the feasibility of a community health promotion programme and its maintenance over a period of 10 years. However, Lenzgesund was not the sole programme in the neighbourhood during the period of observation, so that not all improvements in capacities are directly assignable to the interventions. The instrument mainly reflects the possibly one-sided perspective of the interviewed experts from the community.

Risk of Readmission After Uncomplicated Hospitalization After Radical Cystectomy.

BACKGROUND: Enhanced recovery pathways after radical cystectomy attempt to decrease length of hospitalization, but might increase risk of readmission after discharge. We evaluated the relationship between length of stay and readmission after uncomplicated hospitalization for bladder cancer patients treated with radical cystectomy. PATIENTS AND METHODS: Using the American College of Surgeons National Surgical Quality Improvement Program database, we identified bladder cancer patients who were treated with radical cystectomy from 2011 to 2015. We limited this cohort to those who did not have complications captured while in-hospital, and assessed the proportion readmitted within 30 days of surgery on the basis of length of stay (ie, < 7, 7-9, ≥ 10 days). We fit multivariable logistic regression models to estimate odds of readmission after adjusting for potential confounding factors. RESULTS: Among 4624 patients treated with radical cystectomy, 1003 (21.7%) were readmitted within 30 days of surgery. Of 1,003 readmitted patients, 503 (50%) experienced a major complication after discharge. Factors associated with an increased risk of readmission included diversion with neobladder, diabetes, prolonged surgical time, and obesity (all P < .01). Patients with hospitalization < 7 days were not at increased risk of readmission compared with those with prolonged stays (354/1769, 20.0% < 7 days vs. 201/968, 20.8% ≥ 10 days, adjusted odds ratio, 1.04; 95% confidence interval, 0.90-1.21). CONCLUSION: In the absence of in-hospital complications after radical cystectomy, shorter hospitalizations were not associated with an increased risk of readmission. These findings emphasize the safety and potential cost savings of enhanced recovery pathways after these complex operations.

Myosin light chain kinase knockout improves gut barrier function and confers a survival advantage in polymicrobial sepsis.

Sepsis-induced intestinal hyperpermeability is mediated by disruption of the epithelial tight junction, which is closely associated with the peri-junctional actin-myosin ring. Myosin light chain kinase (MLCK) phosphorylates the myosin regulatory light chain, resulting in increased permeability. The purpose of this study was to determine whether genetic deletion of MLCK would alter gut barrier function and survival from sepsis. MLCK-/- and wild type (WT) mice were subjected to cecal ligation and puncture and assayed for both survival and mechanistic studies. Survival was significantly increased in MLCK-/- mice (95% vs. 24%, p<0.0001). Intestinal permeability increased in septic WT mice compared to unmanipulated mice. In contrast, permeability in septic MLCK-/- mice was similar to that seen in unmanipulated animals. Improved gut barrier function in MLCK-/- mice was associated with increases in the tight junction mediators ZO-1 and claudin 15 without alterations in claudin 1, 2, 3, 4, 5, 7, 8, 13, occludin or JAM-A. Other components of intestinal integrity (apoptosis, proliferation and villus length) were unaffected by MLCK deletion as were local peritoneal inflammation and distant lung injury. Systemic IL-10 was decreased greater than 10-fold in MLCK-/- mice; however, survival was similar between septic MLCK-/- mice given exogenous IL-10 or vehicle. These data demonstrate that deletion of MLCK improves survival following sepsis, associated with normalization of intestinal permeability and selected tight junction proteins.

Predictive Nomogram for Recurrence following Surgery for Nonmetastatic Renal Cell Cancer with Tumor Thrombus.

PURPOSE: Following surgery for nonmetastatic renal cell carcinoma with tumor thrombus the risk of recurrence is significant but variable among patients. The purpose of this study was to develop and validate a predictive nomogram for individual estimation of recurrence risk following surgery for renal cell carcinoma with venous tumor thrombus. MATERIALS AND METHODS: Comprehensive data were collected on patients with nonmetastatic renal cell carcinoma and thrombus treated at a total of 5 institutions from 2000 to 2013. Independent predictors of recurrent renal cell carcinoma from a competing risks analysis were developed into a nomogram. Predictive accuracy was compared between the development and validation cohorts, and between the nomogram and the UISS (UCLA Integrated Staging System, SSIGN (Stage, Size, Grade and Necrosis) and Sorbellini models. RESULTS: A total of 636 patients were analyzed, including the development cohort of 465 and the validation cohort of 171. Independent predictors, including tumor diameter, body mass index, preoperative hemoglobin less than the lower limit of normal, thrombus level, perinephric fat invasion and nonclear cell histology, were developed into a nomogram. Estimated 5-year recurrence-free survival was 49% overall. Five-year recurrence-free survival in patients with 0, 1, 2 and more than 2 risk factors was 77%, 53%, 47% and 20%, respectively. Predictive accuracy was similar in the development and validation cohorts (AUC 0.726 and 0.724, respectively). Predictive accuracy of the thrombus nomogram was higher than that of the UISS (AUC 0.726 vs 0.595, p = 0.001), SSIGN (AUC 0.713 vs 0.612, p = 0.04) and Sorbellini models (AUC 0.709 vs 0.638, p = 0.02). CONCLUSIONS: We present a predictive nomogram for postoperative recurrence in patients with nonmetastatic renal cell carcinoma with venous thrombus. Improving individual postoperative risk assessment may allow for better design and analysis of future adjuvant clinical trials.

Predicting Length of Stay Following Radical Nephrectomy Using the National Surgical Quality Improvement Program Database.

PURPOSE: Length of stay is frequently used to measure the quality of health care, although its predictors are not well studied in urology. We created a predictive model of length of stay after nephrectomy, focusing on preoperative variables. MATERIALS AND METHODS: We used the NSQIP database to evaluate patients older than 18 years who underwent nephrectomy without concomitant procedures from 2007 to 2011. Preoperative factors analyzed for univariate significance in relation to actual length of stay were then included in a multivariable linear regression model. Backward elimination of nonsignificant variables resulted in a final model that was validated in an institutional external patient cohort. RESULTS: Of the 1,527 patients in the NSQIP database 864 were included in the training cohort after exclusions for concomitant procedures or lack of data. Median length of stay was 3 days in the training and validation sets. Univariate analysis revealed 27 significant variables. Backward selection left a final model including the variables age, laparoscopic vs open approach, and preoperative hematocrit and albumin. For every additional year in age, point decrease in hematocrit and point decrease in albumin the length of stay lengthened by a factor of 0.7%, 2.5% and 17.7%, respectively. If an open approach was performed, length of stay increased by 61%. The R(2) value was 0.256. The model was validated in a 427 patient external cohort, which yielded an R(2) value of 0.214. CONCLUSIONS: Age, preoperative hematocrit, preoperative albumin and approach have significant effects on length of stay for patients undergoing nephrectomy. Similar predictive models could prove useful in patient education as well as quality assessment.

Impact of synchronous metastasis distribution on cancer specific survival in renal cell carcinoma after radical nephrectomy with tumor thrombectomy.

PURPOSE: Metastatic renal cell carcinoma can be clinically diverse in terms of the pattern of metastatic disease and response to treatment. We studied the impact of metastasis and location on cancer specific survival. MATERIALS AND METHODS: The records of 2,017 patients with renal cell cancer and tumor thrombus who underwent radical nephrectomy and tumor thrombectomy from 1971 to 2012 at 22 centers in the United States and Europe were analyzed. Number and location of synchronous metastases were compared with respect to patient cancer specific survival. Multivariable Cox regression models were used to quantify the impact of covariates. RESULTS: Lymph node metastasis (155) or distant metastasis (725) was present in 880 (44%) patients. Of the patients with distant disease 385 (53%) had an isolated metastasis. The 5-year cancer specific survival was 51.3% (95% CI 48.6-53.9) for the entire group. On univariable analysis patients with isolated lymph node metastasis had a significantly worse cancer specific survival than those with a solitary distant metastasis. The location of distant metastasis did not have any significant effect on cancer specific survival. On multivariable analysis the presence of lymph node metastasis, isolated distant metastasis and multiple distant metastases were independently associated with cancer specific survival. Moreover higher tumor thrombus level, papillary histology and the use of postoperative systemic therapy were independently associated with worse cancer specific survival. CONCLUSIONS: In our multi-institutional series of patients with renal cell cancer who underwent radical nephrectomy and tumor thrombectomy, almost half of the patients had synchronous lymph node or distant organ metastasis. Survival was superior in patients with solitary distant metastasis compared to isolated lymph node disease.

Trapping by amylose of the aliphatic chain grafted onto chlorogenic acid: importance of the graft position.

5-Caffeoylquinic acid (chlorogenic acid), is classified in acid-phenols family and as polyphenolic compounds it possesses antioxidant activity. The oxydative modification of chlorogenic acid in foods may lead to alteration of their qualities; to counteract these degradation effects, molecular encapsulation was used to protect chlorogenic acid. Amylose can interact strongly with a number of small molecules, including lipids. In order to enable chlorogenic acid complexation by amylose, a C16 aliphatic chain was previously grafted onto the cycle of quinic acid. This work showed that for the two lipophilic derivatives of chlorogenic acid: hexadecyl chlorogenate obtained by alkylation and 3-O-palmitoyl chlorogenic acid obtained by acylation; only the 3-O-palmitoyl chlorogenic acid complexed amylose. The chlorogenic acid derivatives were studied by X-ray diffraction, differential scanning calorimetry and NMR to elucidate the interaction. By comparing the results with previous work on the complexation of amylose by 4-O-palmitoyl chlorogenic acid, the importance of the aliphatic chain position on the cycle of the quinic acid is clearly highlighted. A study in molecular modeling helped to understand the difference in behavior relative to amylose of these three derivatives of chlorogenic acid.

Impact of histologic subtype on cancer-specific survival in patients with renal cell carcinoma and tumor thrombus.

BACKGROUND: Although different prognostic factors for patients with renal cell carcinoma (RCC) and vena cava tumor thrombus (TT) have been studied, the prognostic value of histologic subtype in these patients remains unclear. OBJECTIVE: We analyzed the impact of histologic subtype on cancer-specific survival (CSS). DESIGN, SETTINGS, AND PARTICIPANTS: We retrospectively analyzed the records of 1774 patients with RCC and TT who underwent radical nephrectomy and tumor thrombectomy from 1971 to 2012 at 22 US and European centers. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariable ordered logistic and Cox regression models were used to quantify the impact of tumor histology on CSS. RESULTS AND LIMITATIONS: Overall 5-yr CSS was 53.4% (confidence interval [CI], 50.5-56.2) in the entire group. TT level (according to the Mayo classification of macroscopic venous invasion in RCC) was I in 38.5% of patients, II in 30.6%, III in 17.3%, and IV in 13.5%. Histologic subtypes were clear cell renal cell carcinoma (cRCC) in 89.9% of patients, papillary renal cell carcinoma (pRCC) in 8.5%, and chromophobe RCC in 1.6%. In univariable analysis, pRCC was associated with a significantly worse CSS (p<0.001) compared with cRCC. In multivariable analysis, the presence of pRCC was independently associated with CSS (hazard ratio: 1.62; CI, 1.01-2.61; p<0.05). Higher TT level, positive lymph node status, distant metastasis, and fat invasion were also independently associated with CSS. CONCLUSIONS: In our multi-institutional series, we found that patients with pRCC and vena cava TT who underwent radical nephrectomy and tumor thrombectomy had significantly worse cancer-specific outcomes when compared with patients with other histologic subtypes of RCC. We confirmed that higher TT level and fat invasion were independently associated with reduced CSS.

Septorhinoplasty by disarticulation: early assessment of a new technique for morphological correction of crooked noses.

OBJECTIVE: This study was aimed to assess the early morphological results of a new septorhinoplasty technique based on disarticulation (SRD) between bony and cartilaginous nose structures. METHODOLOGY: A retrospective, multi-judge, blind comparison of pre- and post-operative photographs displayed on Google documents was designed. A nasal morphology analysis grid based on 10 items was fulfilled independently by 6 judges to assess pre- and post-operatively, two times with a 15 day interval, the severity of each deformity by a score between 0 and 2. The sum of all deformities in a single patient produced the individual global score of nasal deformity, which was set between 0 and 20 for each patient. Pre- and post-operative individual global scores were compared using Student`s t test on paired samples. Percentages of post-operative improvement and deterioration were calculated for each item. RESULTS: Thirty-five SRD were analyzed. Before surgery, 80% of noses were humped and 86% were crooked; three months after surgery, 64% of noses had a rectilinear nasal crest on profile and 57% on facial view. The mean global score of deformities drop- ped from 11.1 before surgery to 5.8 after surgery, an improvement of 47% . Improvement rates of 82% and 74.3% were obtained, respectively, for hump profiles and orbitonasal lines. DISCUSSION: The early morphological results of SRD allow to propose this technique as a possible solution to correct crooked noses with humps.

Molecular testing in congenital adrenal hyperplasia due to 21α-hydroxylase deficiency in the era of newborn screening.

Newborn screening (NBS) identifies the majority of classical [salt-wasting (SW) and simple-virilizing (SV)] cases of congenital adrenal hyperplasia (CAH) due to 21α-hydroxylase (21α-OHase) during the first days of life. Diagnosis of classical CAH is confirmed by follow-up serum 17-hydroxyprogesterone and/or the adrenocorticotropin stimulation test; however, neither test definitively distinguishes between the classical subtypes. After confirmation, all newborns are started on hydrocortisone (glucocorticoid) and fludrocortisone (mineralocorticoid) treatment. While initiating fludrocortisone treatment in classical CAH patients, independent of subtype and before SW signs or symptoms occur, prevents a life-threatening SW crisis, it may later complicate distinguishing between the classical subtypes. Genotype-phenotype correlations in 21α-OHase deficiency are excellent; however, molecular testing is not a regular part of the diagnostic workup. Molecular testing on 39 patients (25 identified by NBS) with an already established diagnosis of CAH identified 11 SW patients (8 identified by NBS) whose mutations suggested further biochemical and clinical reassessment of their subtype. Overall, SW accounted for 57.6% of our classical CAH patients, below the generally accepted figure that >75% of classical CAH are comprised of the SW form. In the era of NBS, molecular testing is a valuable supplemental tool identifying patients who may benefit from reassessment of their salt-retaining ability.

Coupling lipophilization and amylose complexation to encapsulate chlorogenic acid.

Chlorogenic acid (5-caffeoylquinic acid) is a hydrophilic phenolic compound with antioxidant properties. Because of its high polarity, these properties may be altered when formulated in oil-based food. There is therefore an interest in trying to protect the natural antioxidant by molecular encapsulation. Amylose, the linear fraction of starch with essentially α(1-4) linkages, is well known for its ability to form semi-crystalline complexes with a variety of small ligands. Monoacyl lipids, as well as smaller ligands such as alcohols or flavor compounds, are able to induce the formation of left-handed amylose single helices. In contrast, chlorogenic acid is a bulky molecule whose topology requires the amylose helix to be distorted, which could prevent amylose complexation. An innovative strategy has been developed to overcome this problem by grafting an aliphatic chain onto chlorogenic acid then trapping this chain in the helical cavity. The lipophilization reaction was used to obtain a palmitoyl chlorogenic acid derivative and the amylose-palmitoyl chlorogenic acid assemblies were studied by X-ray diffraction, differential scanning calorimetry and NMR to elucidate the interaction. The results showed that such interactions between amylose and palmitoyl chlorogenic acid are effective.

Lipase-catalyzed synthesis of two new antioxidants: 4-O- and 3-O-palmitoyl chlorogenic acids.

Chlorogenic acid (5-caffeoyl quinic acid (CQA)) extracted from Hydrangea macrophylla (44%, w/w) with 98% purity, was acylated with palmitic acid by Novozym 435 to yield mono-acylated CQA. Acylation of CQA was achieved in 2-methyl-2-butanol at 60°C, and yielded two mono-acylated products: a major product acylated at the C-4 of the quinic moiety (4-O-palmitoyl chlorogenic acid) and a minor product acylated at the C-3 (3-O-palmitoyl chlorogenic acid). The bioconversions obtained in 7 days ranged from 14 to 60% and were influenced by the molar ratio of palmitic acid/CQA, which ranged from 10 to 80. The regioselectivity (4-O-palmitoyl/3-O-palmitoyl ratio) of the reaction was also affected by the molar ratio, and ranged from 90 to 70%. The scavenging activities against 1,1-diphenyl-2-picryl-hydrazyl radicals demonstrated that these palmitoyl CQA derivatives are associated with antioxidant activity (70% vs CQA).

Gene expression profiling of CD34+ cells identifies a molecular signature of chronic myeloid leukemia blast crisis.

Despite recent success in the treatment of early-stage disease, blastic phase (BP) of chronic myeloid leukemia (CML) that is characterized by rapid expansion of therapy-refractory and differentiation-arrested blasts, remains a therapeutic challenge. The development of resistance upon continuous administration of imatinib mesylate is associated with poor prognosis pointing to the need for alternative therapeutic strategies and a better understanding of the molecular mechanisms underlying disease progression. To identify transcriptional signatures that may explain pathological characteristics and aggressive behavior of BP blasts, we performed comparative gene expression profiling on CD34+ Ph+ cells purified from patients with untreated newly diagnosed chronic phase CML (CP, n=11) and from patients in BP (n=9) using Affymetrix oligonucleotide arrays. Supervised microarray data analysis revealed 114 differentially expressed genes (P<10(-4)), 34 genes displaying more than two-fold transcriptional changes when comparing CP and BP groups. While 24 of these genes were downregulated, 10 genes, especially suppressor of cytokine signalling 2 (SOCS2), CAMPATH-1 antigen (CD52), and four human leukocyte antigen-related genes were strongly overexpressed in BP. Expression of selected genes was validated by real-time-polymerase chain reaction and flow cytometry. Our data suggest the existence of a common gene expression profile of CML-BP and provide new insight into the molecular phenotype of blasts associated with disease progression and high malignancy.